Linezolid Plus Standard of Care (LIPS)

Combination Antibiotic Treatment With Linezolid for Staphylococcus Aureus Bacteraemia: a Randomised Controlled Trial

The aim of the study is to assess whether targeting virulence factors by administering linezolid in addition to standard antibiotic treatment improves outcomes in patients with Staphylococcus aureus bacteraemia.

Study Overview

• Status: Recruiting
• Conditions: Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)
• Intervention / Treatment: Drug: Linezolid 600 mg; Drug: Placebo

Detailed Description

Staphylococcus aureus (S. aureus) is one of the deadliest bacterial pathogens, especially in high-income countries, and causes bloodstream infections (bacteraemia) in 20-30 per 100,000 people annually. Despite widely available antibiotic treatments, the 90-day mortality rate remains high at 20-30%, and complications such as organ damage, relapses, and long-term impairment affect many survivors. Existing treatments have failed to improve survival rates highlighting the urgent need for novel therapeutic strategies.

Virulence factors produced by S. aureus facilitate bacterial persistence and spread, and tissue damage. Preclinical research suggests that inhibiting the production of virulence factors may improve patient outcomes. While some clinical guidelines recommend this approach for toxin-mediated infections, randomized controlled trials (RCTs) evaluating this approach in S. aureus bacteraemia have not yet been conducted.

Linezolid, an antibiotic commonly used for pneumonia and complicated skin and soft-tissue infections, has shown strong inhibition of the expression of S. aureus virulence factors in preclinical studies. Studies in animal models demonstrated that linezolid, when combined with other antibiotics, enhances treatment efficacy and reduces bacterial toxin production. Observational studies suggest that early initiation of linezolid may lead to better patient outcomes, but no RCT has tested this approach in S. aureus bacteraemia.

This placebo-controlled trial will evaluate whether adding a 5-day course of linezolid to standard antibiotic therapy improves clinical outcomes in patients with S. aureus bacteraemia.

• Study Type: Interventional
• Enrollment (Estimated): 606
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Natalie Rose, PhD; Phone Number: +41 61 328 35 54; Email: natalie.rose@usb.ch
• Study Contact Backup: Name: Richard Kühl, PD Dr. med.; Phone Number: +41 61 328 66 61; Email: richardalexander.kuehl@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel (USB)
    • Contact: Natalie Rose, PhD; Phone Number: +41 61 328 35 54; Email: natalie.rose@usb.ch
    • Principal Investigator: Richard Kühl, PD Dr. med.
  • Bern, Switzerland
    • Not yet recruiting
    • Inselspital Bern
    • Principal Investigator: Christine Thurnheer, PD Dr. med.
  • Sankt Gallen, Switzerland
    • Not yet recruiting
    • HOCH Health Ostschweiz, Kantonsspital St.Gallen
    • Principal Investigator: Werner Albrich, Prof. Dr. med.
  • Zurich, Switzerland
    • Recruiting
    • Universitätsspital Zürich (USZ)
    • Principal Investigator: Barbara Hasse, Prof. Dr. med.
  • Zurich, Switzerland
    • Recruiting
    • Stadtspital Zürich Triemli
    • Principal Investigator: Adrian Schibli, Dr. med.
  • Canton Ticino
    • Lugano, Canton Ticino, Switzerland
      • Recruiting
      • Ente Ospedaliero Cantonale (EOC)
      • Principal Investigator: Marco Bongiovanni, PD Dr. med.
  • Canton of Aargau
    • Aarau, Canton of Aargau, Switzerland
      • Recruiting
      • Kantonsspital Aarau (KSA)
      • Principal Investigator: Anna Conen, PD Dr. med. MSc.
  • Canton of Basel-City
    • Basel, Canton of Basel-City, Switzerland
      • Recruiting
      • St. Claraspital
      • Principal Investigator: Elisabeth Wehrle-Wieland, Dr. med.
  • Canton of Geneva
    • Geneva, Canton of Geneva, Switzerland
      • Not yet recruiting
      • Hôpitaux Universitaires de Genève (HUG)
      • Principal Investigator: Stephan Harbarth, Prof. Dr. med.
  • Canton of Jura
    • Delémont, Canton of Jura, Switzerland
      • Not yet recruiting
      • Hôpital du Jura
      • Principal Investigator: Michèle Birrer, Dre
  • Canton of Vaud
    • Lausanne, Canton of Vaud, Switzerland
      • Not yet recruiting
      • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Principal Investigator: Matthaios Papadimitriou-Olivgeris, PD Dr. med. PhD
  • Canton of Zurich
    • Winterthur, Canton of Zurich, Switzerland
      • Not yet recruiting
      • Kantonsspital Winterthur (KSW)
      • Principal Investigator: Urs Karrer, PD Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Staphylococcus aureus (S. aureus) grown from at least one blood culture
• Hospitalised at a participating centre
• ≥18 years old
• Written informed consent or fulfilling criteria for an emergency exception from informed consent requirements

Exclusion criteria:

• Administration of the initial drug treatment not feasible within 72 hours since the collection of the first positive blood culture with S. aureus
• Documented history of positive blood cultures for S. aureus occurring between 72 hours and 180 days prior to the eligibility assessment
• Necrotising fasciitis
• Currently receiving linezolid or clindamycin
• Use of any monoamine oxidase A or B inhibitor within the last two weeks
• Known hypersensitivity to linezolid or any other ingredients of the study drugs
• Current severe thrombocytopenia (i.e. <30 x 10^9/L)
• Application of study drug not possible (per mouth or per gastric tube)
• Currently breastfeeding
• Local treating team believes that death is imminent and inevitable
• Patient is receiving end of life care and antibiotic treatment is not considered appropriate
• Local treating team believes that participation in the study is not in the best interest of the patient
• Any indication that the patient is unwilling to participate in the study including an advance directive stating such unwillingness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linezolid; 600mg twice a day for 5 days (in addition to the standard antibiotic treatment)	Drug: Linezolid 600 mg; linezolid 600 mg tablets (twice a day for 5 days)
Placebo Comparator: Placebo; oral placebo tablets twice a day for 5 days (in addition to the standard antibiotic treatment)	Drug: Placebo; Placebo tablets (twice a day for 5 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Desirability of Outcome Ranking (DOOR)	The hierarchical composite endpoint DOOR will be calculated based on the following 4 criteria: Alive at 90 days; Return to usual level of function by day 90; None of the following complications: Microbiological or clinical failure leading to treatment change; Serious adverse reaction; Adverse event leading to study drug discontinuation; Hospital length of stay The primary outcome will be expressed as the win ratio, i.e., the ratio of the number of times that participants in the intervention group have a lower DOOR compared to those in the control group. In this study, a pairwise comparison is used, i.e., every participant in the linezolid group is compared with every participant in the control group. When comparing two participants, the winner will be determined by the first component of the DOOR in which the two participants differ, the only exceptions being ties when both participants die or if they do not die but have the same length of hospitalisation.	From randomisation (day 1) until day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	Proportion of patients who died from any cause during the duration of the study.	From randomisation (day 1) until day 90
Time to death		From randomisation (day 1) until day 90
Level of function	Proportion of participants back to their usual level of function prior to the infection.	From randomisation (day 1) until day 90
Number of participants with microbiological failure leading to treatment change	Any positive sterile site culture with Staphylococcus aureus (S. aureus) between 14 and 90 days after randomisation that leads to a change in treatment. A sterile site means any site of the body where microorganisms are usually absent, i.e. below the outer and inner colonised surfaces of the skin and mucous membranes. Positive sterile sites cultures include deep visceral and musculoskeletal abscesses obtained in a sterile manner.	From day 14 to day 90 (randomisation = day 1)
Number of participants with early microbiological failure leading to treatment change	Any positive sterile site culture with S. aureus between 5 and 13 days after randomisation that leads to a change in treatment. A sterile site means any site of the body where microorganisms are usually absent, i.e. below the outer and inner colonised surfaces of the skin and mucous membranes. Positive sterile sites cultures include deep visceral and musculoskeletal abscesses obtained in a sterile manner.	From day 5 to day 13 (randomisation = day 1)
Number of participants with clinical failure leading to treatment change	Newly identified focus of S. aureus between 14 and 90 days after randomisation as determined by the site investigator (or delegated physician) that leads to a change in treatment. This can incorporate clinical, radiological, microbiological and pathological findings.	From day 14 to day 90 (randomisation = day 1)
Number of participants with early clinical failure leading to treatment change	Newly identified focus of S. aureus between 5 and 13 days after randomisation as determined by the site investigator (or delegated physician) that leads to a change in treatment. This can incorporate clinical, radiological, microbiological and pathological findings.	From day 5 to day 13 (randomisation = day 1)
Hospital length of stay	Duration of the index acute hospital stay from randomisation until the day of hospital discharge. Transfers to another acute care hospital for continuation of acute treatment will be included in the assessment of hospital length of stay. Days after transfer to rehabilitation centres or switch to outpatient parenteral ambulatory treatment will not be included in the acute hospital stay.	From randomisation (day 1) until day 90
Time to being discharged alive	For participants who die during the hospitalisation, 90 days will be recorded.	From randomisation (day 1) until day 90
Days alive without being on the Intensive Care Unit (ICU)	Number of days a participant is alive and not hospitalised in the Intensive Care Unit.	From randomisation (day 1) until day 90
Days alive without antibiotics	Number of days a participant is alive and not on any antibiotics.	From randomisation (day 1) until day 90
Physical health	Physical health assessed by patient-reported outcome using SF-36 questionnaire. The SF-36 questionnaire score ranges from 0 to 100, with higher scores indicating better health.	At day 90 (randomisation = day 1)
Number of participants with persistent bacteraemia	S. aureus-positive blood culture on day 5 (±1 day) after randomisation. If day 2 or day 3 blood cultures are negative and no subsequent blood cultures are performed, the day 5 blood culture is presumed to be negative.	At day 5 (randomisation = day 1)
Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled	SIRS criteria: Abnormal body temperature (<36°C or >38°C); tachypnoea or mechanical ventilation (RR>20 breaths per minute); tachycardia (HR >90 beats per minute in an adult; abnormal leukocyte count (from routine blood sampling on day 5 ±1 day, defined as >12.0 x 10^9/L or <4.0 x 10^9/L or >10% of immature (band) forms)	At day 5 (randomisation = day 1)
Change in C-reactive protein (CRP)	Day 1 CRP means any blood CRP measurement taken on randomisation day 1 or the calendar day prior to randomisation. If there is more than one measurement, the value recorded is the one taken closest before randomisation.	From randomisation (day 1) until day 5
Development of new antibiotic drug resistance in Staphylococcus aureus	Any new resistance absent in the S. aureus from the initial blood culture and detected in any S. aureus cultured after the start of the intervention.	From randomisation (day 1) until day 90
Adverse events leading to study drug discontinuation	Any adverse event (irrespective of grade) leading to study drug discontinuation as documented by the treating physician.	From randomisation (day 1) until day 5
Serious adverse reactions until day 90	Any serious adverse event will be reported to the study-site principal investigator, who then assesses whether there is a reasonable causal relationship with the investigational medicinal product.	From randomisation (day 1) until day 90
Clinical signs of serotonin toxicity	Assessed using the Hunter Serotonin Toxicity Criteria.	From randomisation (day 1) until day 7
Laboratory signs of myelosuppression	Laboratory confirmation of thrombocytopenia, anaemia, or leukopenia.	From randomisation (day 1) until day 7
Evidence of hyperlactatemia	In case of clinical suspicion of hyperlactatemia, lactate levels will be measured and compared to specific laboratory-defined reference ranges. For increased lactate levels, the causality with the study treatment will be assessed.	From randomisation (day 1) until day 7
Acute kidney injury	Assessed on day 5 and, if participant remains hospitalised, on day 14, using the Kidney Disease Improving Global Outcomes (KDIGO) definition.	From randomisation until day 14
Number of participants with Clostridioides difficile (C. difficile)-associated diarrhoea	This means a stool submitted to a clinical laboratory has tested positive for C. difficile toxin or toxin gene.	From randomisation (day 1) until day 90
Mental health	Mental health assessed by patient-reported outcome using Short Form-36 (SF-36) questionnaire. The SF-36 questionnaire score ranges from 0 to 100, with higher scores indicating better health.	At day 90 (randomisation = day 1)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Linezolid trough plasma concentrations at day 4 or 5	Additional exploratory laboratory outcome for a subset of participants only in participating centres (results may be reported in a publication separate from the publication of the main study results).	At day 5 (day of randomisation = day 1)
Molecular mechanisms of S. aureus bacteraemia	Basic research on the location of S. aureus in human blood (extracellular or intracellular). This will be conducted in a sub-sample of participants consenting to additional blood sampling and published separately from the publication of the main study results.	From randomisation (day 1) until day 90 or until the date of the participant's first blood culture negative for S. aureus, whichever came first.

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Benjamin Speich, PD, PhD, University Hospital, Basel, Switzerland; Principal Investigator: Richard Kühl, PD Dr. med., University Hospital, Basel, Switzerland; Principal Investigator: Nina Khanna, Prof. Dr. med., University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2025
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: April 1, 2025
• First Submitted That Met QC Criteria: April 25, 2025
• First Posted (Actual): May 6, 2025

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Bacteremia; Staphylococcus aureus; Bloodstream Infection; Linezolid; Bacteraemia; Methicillin-resistant Staphylococcus aureus (MRSA); Methicillin-susceptible Staphylococcus aureus (MSSA); Penicillin-susceptible Staphylococcus aureus (PSSA); Virulence factors; Hierarchical composite endpoint
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pathological Conditions, Signs and Symptoms; Staphylococcal Infections; Bacteremia; Sepsis; Toxemia; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Acids, Acyclic; Carboxylic Acids; Amides; Acetamides; Acetates; Oxazolidinones; Oxazoles; Linezolid
• Other Study ID Numbers: 2025-00655; am23Khanna3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After publication of the main results, the full dataset will be submitted to the Data Access Committee of the Faculty of Medicine (MF-DAC) at the University of Basel. Other researchers interested in using the study data may contact the independent MF-DAC of the University of Basel to request access.
• IPD Sharing Time Frame: A detailed statistical analysis plan will be finalised before database lock. The statistical analysis plan will be made publicly available on clinicaltrials.gov.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No